Asthma is a chronic inflammatory disorder of the airways in which inflammation contributes to hyper responsiveness to allergic and irritant stimuli, to airflow limitation, to a broad spectrum of respiratory symptoms, and to disease chronicity. Features of this inflammatory process include denudation of airway epithelium, edema, recruitment and activation of various types of migratory inflammatory cells, and increased basement membrane collagen deposition which is believed to be the cause of the chronic changes known as asthmatic airway remodeling.
Topically acting corticosteroids are the most potent and consistently effective long-term control medication for asthma. Their broad action on the inflammatory process may account for their efficacy as preventive therapy. Their clinical effects include reduction in severity of symptoms, improvement in peak expiratory flow rate and spirometry, diminished hyper responsiveness of airways, prevention of exacerbations, and possibly the prevention of airway wall remodeling. Further, there are data suggesting that earlier treatment with inhaled topically acting steroids, measured in years following diagnosis of asthma, results in better long term outcome and lower cumulative aggregate dose of steroids needed for optimal control.
Topically acting corticosteroids for asthma are generally administered as aerosolized droplets released into a spacer or holding chamber from a pressurized metered dose inhaler, and slowly inhaled from expiration or resting lung volume to maximum inspiratory volume by the patient, who then holds his breath for at least 10 seconds. Alternative devices are dry powder inhalers, activated by sucking from expiration or resting lung volume to maximal inspiration, followed by similar breath-holding.
The most widely favored delivery system for inhaled asthma medications for children who are too young to effectively use metered dose aerosols or dry powders, and for patients of any age whose airways are so irritable that they will cough out medications inhaled from metered dose or dry powder inhalers, is the compressor-driven jet nebulizer. This device generates a mist of droplets of medication in aqueous solution which is inhaled through either a mouthpiece or a mask. The market for this type of drug delivery system is large enough to have supported the development of inexpensive equipment for home use that is easy to use and reasonably efficient at delivering particles in the size range needed for effective topical treatment of asthma. The distribution system for this type of equipment makes it available at competitive prices throughout the United States. There are also other types of nebulizers designed for the same market, one being ultrasonic, in which mist is generated by a small plate vibrating at ultrasonic frequency instead of by turbulence created by a jet of compressed air. Some may become more popular in the future as ways to generate aerosols with different particle size distribution. It is anticipated that most will be designed to compete with the jet nebulizer market, for nebulization of liquids with nebulization characteristics approximating those of physiologic saline, and in volumes of 1 to 5 ml.
Topically acting corticosteroids are not sufficiently water-soluble to deliver effective treatment doses in practical volumes of nebulizable solution. This makes the most potent and consistently effective long-term control medications for asthma unavailable to young children, for whom early treatment with these medications offers the greatest potential for long term reduction in severity.
There have been previous attempts to overcome this problem.
Metered dose aerosol holding chambers have been designed with valves and masks, to be placed over a child's mouth and nose, so that droplets of medication sprayed into the chamber from an “adult” metered dose asthma inhaler will be inhaled in the course of either the child's normal breathing, or (as many young children resist the devices) the child's crying. Some parents, some physicians and some investigators find these devices convenient and effective, many find them much less so.
Unit doses of small, readily absorbable particles of water-insoluble, topically-acting steroids have been packaged with aqueous vehicles for nebulizer administration as aqueous suspensions. Such products have shelf life stability problems because of agglomeration of small drug particles into larger ones over time.
The recently published international PCT application WO 99/44594 discloses a drug delivery system in which water-insoluble drugs are prepared as lipid-water emulsions, freeze-dried, and dispersed in water for nebulization. Emulsions, like suspensions, are two-phase systems which, over time, undergo physical transition to lower energy states. Maintenance of a boundary between phases takes energy, so that a lower energy state can be achieved by reducing the surface area of this boundary. For a solid-in-liquid suspension the physical transition that takes place over time is particle agglomeration. For an emulsion, it is dissociation.
The present invention is an application of a model based on principles of physical chemistry, for the design of formulations of topically acting corticosteroids and other water-insoluble drugs for nebulizer inhalation in aqueous vehicles, which avoid the problems of particle agglomeration and dissociation of emulsions. The present invention also allows the economy of multiple dose packaging of concentrated drug in a state that is both ready-to-use and physically stable.